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Background & Aims: Minimal hepatic encephalopathy (MHE) has been linked to higher real-life rates of automobile crashes and poor performance in driving simulation studies, but the link between driving simulator performance and real-life automobile crashes has not been clearly established. Furthermore, not all patients with MHE are unsafe drivers, but it is unclear how to distinguish them from unsafe drivers. We investigated the link between performance on driving simulators and real-life automobile accidents and traffic violations. We also aimed to identify features of unsafe drivers with cirrhosis and evaluated changes in simulated driving skills and MHE status after 1 year. Methods: We performed a study of outpatients with cirrhosis (n = 205; median 55 years old; median model for end-stage liver disease score, 9.5; none with overt hepatic encephalopathy or alcohol or illicit drug use within previous 6 months) seen at the Virginia Commonwealth University and McGuire Veterans Administration Medical Center, from November 2008 through April 2014. All participants were given paper-pencil tests to diagnose MHE (98 had MHE; 48%), and 163 patients completed a standardized driving simulation. Data were collected on traffic violations and automobile accidents from the Virginia Department of Motor Vehicles and from participants' self-assessments when they entered the study, and from 73 participants 1 year later. Participants also completed a questionnaire about alcohol use and cessation patterns. The driving simulator measured crashes, run-time, road center and edge excursions, and illegal turns during navigation; before and after each driving simulation session, patients were asked to rate their overall driving skills. Drivers were classified as safe or unsafe based on crashes and violations reported on official driving records; simulation results were compared with real-life driving records. Multivariable regression analyses of real-life crashes and violations was performed using data on demographics, cirrhosis details, MHE status, and alcohol cessation patterns, at baseline and at 1 year. Results: Drivers categorized as unsafe had more crashes and made more illegal turns on the driving simulator than drivers categorized as safe; a higher proportion of subjects with MHE were categorized as unsafe drivers at baseline (16%) than subjects without MHE (7%; P =02), and at 1-year follow-up (18% vs 0%; P =02). Alcohol cessation within

The functional basis of cognitive and quality of life changes after liver transplant is unclear. We aimed to evaluate the neurometabolic and functional brain changes as modulators of cognition and quality of life after transplant in patients with cirrhosis who were with/without pretransplant cognitive impairment and hepatic encephalopathy (HE). Patients with cirrhosis underwent detailed cognitive and quality of life assessment at enrollment and 6 months after transplant. A subset underwent brain magnetic resonance imaging (functional magnetic resonance imaging [fMRI], diffusion tensor imaging [DTI], and magnetic resonance spectroscopy [MRS]) before and after transplant. Changes before and after transplant were analyzed in all patients and by dividing groups in those with/without pretransplant cognitive impairment or with/without pretransplant HE. MRS evaluated ammonia-related metabolites; fMRI studied brain activation for correct lure inhibition on the inhibitory control test; and DTI studied white matter integrity. Sixty-six patients (mean Model for End-Stage Liver Disease score, 21.8; 38 HE patients and 24 cognitively impaired [CI] patients) were enrolled. Quality of life was significantly worse in CI and HE groups before transplant, which improved to a lesser extent in those with prior cognitive impairment. In the entire group after transplant, there was (1) significantly lower brain activation needed for lure inhibition (shown on fMRI); (2) reversal of pretransplant ammonia-associated changes (shown on MRS); and (3) improved white matter integrity (shown on DTI). Importantly, study findings suggest that pretransplant cognitive impairment serves as a marker for clinical outcomes. Regardless of pretransplant history of HE, it was the pretransplant cognitive impairment that was predictive of both posttransplant cognitive and psychosocial outcomes. Therefore, when working with patients and their families, a clinician may rely on the pretransplant cognitive profile to develop expectations regarding posttransplant neurobehavioral recovery. We conclude that functional brain changes after liver transplant depend on pretransplant cognitive impairment and are ultimately linked with posttransplant cognition and quality of life in cirrhosis. Liver Transplantation 22 1379-1390 2016 AASLD.

Health-related quality of life (HRQOL) is an important determinant of prognosis in cirrhosis and hepatic encephalopathy (HE). However due to inherent cognitive dysfunction, insight into HRQOL severity in patients with liver disease may be impaired. To assess insight into HRQOL using PROMIS tools compared to norms in cirrhotic patients. PROMIS tools are validated HRQOL instruments that test the domains of anger, anxiety, depression, physical function, pain behavior/impact, sleep disturbances/impairment, and social activities/roles, compared to US-norms. Patients were administered the PROMIS tools, the results of which were reviewed using a visual comparison with thed norms. Then two Likert scales from 0 to 10 per domain were administered that inquired about (1) Surprise Intensity: 0–4: not surprised, 5–10: surprised; and (2) Expectancies: 0–4: results better than expected, 5:10: as/worse than expected. Comparisons between HE/no-HE were also performed. 203 cirrhotic patients (57 yrs., 62 % men, MELD 12, 83 HE) were included. All HE patients were controlled on therapy. Prior HE patients were significantly impaired on all PROMIS domains (p < 0.01) except anger, compared to the re st. The majority (76–85 %) were not surprised with their placement vis-a-vis the norms. Similarly, a majority (59–61 %) thought their results were worse or as expected. However, a third of patients found that their PROMIS results were better than expected. Prior HE status did not significantly impact expectations or surprise based on placement with the norms. The majority of cirrhotic patients, regardless of prior HE, have good insight regarding their HRQOL issues.

Nonalcoholic fatty liver disease is becoming an epidemic. Fat is typically stored in adipose tissue in the form of triglycerides (TGs). The deposition of TGs in the liver is the result of an imbalance between the amount of energy taken in and the amount used. This balance is maintained by a complex interplay between the dietary intake of nutrients, the hormonal response to the nutrients, and their effect on both the liver and adipose tissue. Disruption of this system is what leads to the development of steatosis and is the focus of this article.

Background Hepatitis B immune globulin (HBIg) with or without nucleos(t)ide analogue (NA) inhibitors has been shown to prevent recurrence of hepatitis B virus (HBV) following orthotopic liver transplantation (OLT). However, the use of HBIg has many disadvantages. Aims The present study was performed to determine if converting patients from HBIg±NA to combination NA therapy could prevent recurrence of HBV. Methods Twenty-one recipients without evidence of HBV recurrence on HBIg±NA for ≥6 months were enrolled. Patients received their last injection of HBIg at the time they initiated tenofovir disoproxil fumarate/emtricitabine (TDF/FTC; Truvada®) and were followed up for 31.1 ± 9.0 [range 15–47] months. Results After 1 year, 3 patients (14%) had detectable HBsAg, one of whom was non-compliant. Two of 3 with recurrence cleared HBsAg by last follow-up on TDF/FTC; the non-compliant patient became HBV DNA-undetectable with re-institution of TDF/FTC. TDF/FTC saved $12,469/year over our standard-of-care, monthly intramuscular HBIg/lamivudine. There was no evidence of a general adverse effect of TDF/FTC on renal function. However, 3 patients developed reversible acute renal failure; on renal biopsy, 1 had possible TDF/FTC-induced acute tubular necrosis. Conclusions Substitution of TDF/FTC for HBIg prevented recurrence of HBV DNA in 100% (20/20) of patients who were compliant with the medication and led to substantial cost savings over HBIg-containing regimens.

Background & Aims Patients with acute liver injury/failure (ALI/ALF) are assumed to have a bleeding diathesis on the basis of elevated INR; however, clinically significant bleeding is rare. We hypothesized that patients with ALI/ALF have normal hemostasis despite elevated INR. Methods Fifty-one patients with ALI/ALF were studied prospectively using thromboelastography (TEG), which measures the dynamics and physical properties of clot formation in whole blood. ALI was defined as an INR ⩾1.5 in a patient with no previous liver disease, and ALF as ALI with hepatic encephalopathy. Results Thirty-seven of 51 patients (73%) had ALF and 22 patients (43%) underwent liver transplantation or died. Despite a mean INR of 3.4±1.7 (range 1.5–9.6), mean TEG parameters were normal, and 5 individual TEG parameters were normal in 32 (63%). Low maximum amplitude, the measure of ultimate clot strength, was confined to patients with platelet counts 9 /L. Maximum amplitude was higher in patients with ALF than ALI and correlated directly with venous ammonia concentrations and with increasing severity of liver injury assessed by elements of the systemic inflammatory response syndrome. All patients had markedly decreased procoagulant factor V and VII levels, which were proportional to decreases in anticoagulant proteins and inversely proportional to elevated factor VIII levels. Conclusions Despite elevated INR, most patients with ALI/ALF maintain normal hemostasis by TEG, the mechanisms of which include an increase in clot strength with increasing severity of liver injury, increased factor VIII levels, and a commensurate decline in pro- and anticoagulant proteins.

SUMMARY Background Cirrhotic patients have an impaired health-related quality of life (HRQOL), which is usually analysed using static paper-pencil questionnaires. The Patient Reported Outcomes Measurement Information System (PROMIS) computerised adaptive testing (CAT) are flexible, freely available, noncopyrighted, HRQOL instruments with US-based norms across 11 domains. CAT presents five to seven questions ⁄ domain depending on the patient’s response, from large validated question banks. This provides brevity and precision equivalent to the entire question bank.

Though, a number of studies regarding the analysis of firearm discharge residue (FDR) particles have been conducted globally for range estimation by utilizing cartridges of various makes and origin, but in this paper, we have conducted several firings using ammunition manufactured by Indian Ordnance Factories and studied the presence of inorganic constituents contributed by priming mixture, cartridge case and bullet for this purpose. It has been found that there is atleast one element which can be used for range estimation irrespective of its origin from priming mixture, cartridge case or bullet.

Alcoholic hepatitis (AH) develops in a small percentage of heavy drinkers. The adaptive immune system of AH patients is hyper-activated, yet dysregulated and ineffective against infectious diseases. Mucosal-associated invariant T (MAIT) cells are innate-like lymphocytes that are found in liver, intestinal mucosa, and peripheral blood and contribute to protection against infectious diseases. To determine whether MAIT cells were dysregulated in heavy drinkers and the effect of alcohol abstinence on MAIT cell recovery, we compared peripheral MAIT cells between AH patients and heavy drinkers without liver disease (HDC) at baseline and 6- and 12-month followup. At baseline, AH patients had severely reduced frequency of MAIT cells than HDC and healthy donor controls (HC), whereas MAIT cell frequency was not significantly different between HDC and HC. In addition, MAIT cells in AH patients expressed higher levels of the activation markers (CD69, CD38, and HLA-DR) as well as the immune checkpoint inhibitor PD-1. Multiplex immunoassays showed that plasma levels of several cytokines related to MAIT cell activation were elevated in AH patients (IFN-s, IL-7, IL-15, IL-17, IL-18, and IL-23, and TNF-a). In AH patients, the frequency MAIT cells and CD38-expressing MAIT cells correlated with levels of several cytokines and AST. At followup, AH patients had increased MAIT cell frequency and decreased MAIT cell activation with cessation of alcohol. However, abstinent AH patients still had higher levels of CD38-expressing MAIT cells than HDC at 6-month followup. Conclusion Blood MAIT cells were severely reduced and were dysregulated in AH patients and alcohol abstinence partially reversed abnormalities in MAIT cell frequency and phenotype.

Specific alterations in hepatic lipid composition characterize the spectrum of nonalcoholic fatty liver disease (NAFLD), which extends from nonalcoholic fatty liver (NAFL) to nonalcoholic steatohepatitis (NASH). However, the plasma lipidome of NAFLD and whether NASH has a distinct plasma lipidomic signature are unknown. A comprehensive analysis of plasma lipids and eicosanoid metabolites quantified by mass spectrometry was performed in NAFL (n = 25) and NASH (n = 50) subjects and compared with lean normal controls (n = 50). The key findings include significantly increased total plasma monounsaturated fatty acids driven by palmitoleic (16:1 n7) and oleic (18:1 n9) acids content (P < 0.01 for both acids in both NAFL and NASH). The levels of palmitoleic acid, oleic acid, and palmitoleic acid to palmitic acid (16:0) ratio were significantly increased in NAFLD across multiple lipid classes. Linoleic acid (8:2n6) was decreased (P < 0.05), with a concomitant increase in γ-linolenic (18:3n6) and dihomo γ-linolenic (20:3n6) acids in both NAFL and NASH (P < 0.001 for most lipid classes). The docosahexanoic acid (22:6 n3) to docosapentenoic acid (22:5n3) ratio was significantly decreased within phosphatidylcholine (PC), and phosphatidylethanolamine (PE) pools, which was most marked in NASH subjects (P < 0.01 for PC and P < 0.001 for PE). The total plasmalogen levels were significantly decreased in NASH compared with controls (P < 0.05). A stepwise increase in lipoxygenase (LOX) metabolites 5(S)-hydroxyeicosatetraenoic acid (5-HETE), 8-HETE, and 15-HETE characterized progression from normal to NAFL to NASH. The level of 11-HETE, a nonenzymatic oxidation product of arachidonic (20:4) acid, was significantly increased in NASH only. Conclusions: Although increased lipogenesis, desaturases, and LOX activities characterize NAFL and NASH, impaired peroxisomal polyunsaturated fatty acid (PUFA) metabolism and nonenzymatic oxidation is associated with progression to NASH.

Background & Aims: Nonalcoholic fatty liver (NAFL) and nonalcoholic steatohepatitis (NASH) are associated with known triggers of the unfolded protein response (UPR). The aims were to (1) evaluate the activity of UPR in NAFL and NASH and (2) correlate expression of UPR pathways with liver histology. Methods: Messenger RNA (mRNA) and protein expression were measured by quantitative real-time PCR and Western blot, respectively. Apoptosis was assessed by TUNEL assay. Liver histology was scored using the NASH clinical research network criteria. Results: Compared with subjects with the metabolic syndrome and normal liver histology (n = 17), both NAFL (n = 21) and NASH (n = 21) were associated with increased eukaryotic initiation factor-2α (eIF-2α) phosphorylation. Activating transcription factor 4 (ATF4) mRNA and protein, C/EBP homologous protein (CHOP), and growth arrest, DNA damage-34 (GADD34) mRNA were not increased in NAFL or NASH. Whereas immunoglobulin heavy chain binding protein mRNA was significantly increased in NASH, unspliced X-box protein-1 (XBP-1) protein did not increase. Also, endoplasmic reticulum degradation-enhancing α-mannosidase-like protein mRNA levels were inversely related to spliced XBP-1 mRNA in NASH. NASH was specifically associated with low sXBP-1 protein and increased JNK phosphorylation. This correlated with increased TUNEL activity in NASH. The histologic severity correlated with sXBP-1 mRNA and JNK phosphorylation. Conclusions: There is a variable degree of UPR activation in NAFL and NASH. Although both NAFL and NASH are associated with eIF-2α phosphorylation, there is a failure to activate downstream recovery pathways, ie, ATF4-CHOP-GADD34. NASH is specifically associated with (1) failure to generate sXBP-1 protein and (2) activation of JNK.

The Veteran’s Affairs Cooperative Group Studies in the 1990s established that the majority of patients with severe alcoholic hepatitis have protein-calorie malnutrition.1 Protein-calorie malnutrition, assessed using 8 nutritional parameters, is associated with significantly higher 30-day, 6-month, and 12-month mortality rates.2 Preadmission malnutrition is exacerbated by a marked catabolic state in many patients with alcoholic hepatitis.3 Consequently, guidelines published by the American Association for Study of Liver Disease and the European Association for Study of the Liver recommend enteral nutritional therapy.4,5 Enteral nutrition with goal of 35–40 kcal/kg of body weight (BW) and a daily protein intake of 1.2–1.5 g/kg of BW in patients with liver disease is recommended by the European Society for Clinical Nutrition and Metabolism guidelines.6 Existing evidence favors that early enteral nutrition can significantly benefit morbidity and mortality in severe disease state such as critical illness.6 The mechanisms that can confer enteral nutrition benefits include preserving the intestinal barrier and decreasing intestinal permeability, immune modulation, and decreasing risk of infection. In addition, enteral nutrition supplementation can preserve further muscle loss and prevent worsening sarcopenia, promote anabolism, and replete glutathione stores that are often depleted in chronic alcoholics including those with alcoholic hepatitis. Nevertheless, the evidence supporting the use of enteral nutrition is not strong.7 In this issue of Gastroenterology, Moreno et al8 report the results of an important randomized trial comparing intense enteral nutrition with conventional nutrition. The trial population was patients with biopsy confirmed severe alcoholic hepatitis with a discriminant function of ≥32. Intensive nutrition consisted of 1500 kcal, 75 g protein, 170 g carbohydrate, and 58 g fat per liter delivered by feeding tube at 1 L/d for BW 90 kg. All patients received corticosteroids for 28 days and the primary outcome measure was mortality at 6 months. At first glance, this seems to be a negative study with no difference in the primary outcome measure. However, there is a lot to learn from this study about the management of patients with this condition. Although not significant, the mortality rate at 1 and 6 months was lower in the intensive nutrition group compared with the control group; 44.4% versus 52.1% at 6 months and 16.2% versus 20.7% at 1 month. Potentially, as highlighted by the authors themselves, there is a type II statistical error here owing to the trial being underpowered. A 10% difference in the 6-month survival may realistically be feasible, but the sample size required to confirm this statistically would be enormous. An important message from the trial is that nutritional intake, irrespective of the treatment arm, is a major determinant of mortality. Those patients receiving

The spectrum of nonalcoholic fatty liver disease (NAFLD) includes a nonalcoholic fatty liver (NAFL) and nonalcoholic steatohepatitis (NASH). The specific types and amounts of lipids that accumulate in NAFLD are not fully defined. The free fatty acid (FFA), diacylglycerol (DAG), triacylglycerol (TAG), free cholesterol (FC), cholesterol ester, and phospholipid contents in normal livers were quantified and compared to those of NAFL and NASH, and the distribution of fatty acids within these classes was compared across these groups. Hepatic lipids were quantified by capillary gas chromatography. The mean (nmol/g of tissue) DAG (normal/NAFL/NASH: 1922 versus 4947 versus 3304) and TAG (13,609 versus 128,585 versus 104,036) increased significantly in NAFLD, but FFA remained unaltered (5533 versus 5929 versus 6115). There was a stepwise increase in the mean TAG/DAG ratio from normal livers to NAFL to NASH (7 versus 26 versus 31, P0.001). There was also a similar stepwise increment in hepatic FC (7539 versus 10,383 versus 12,863, P0.05 for NASH). The total phosphatidylcholine (PC) decreased in both NAFL and NASH. The FC/PC ratio increased progressively (0.34 versus 0.69 versus 0.71, P0.008 for both). Although the levels for linoleic acid (18:2n-6) and alpha-linolenic acid (18:3n-3) remained unaltered, there was a decrease in arachidonic acid (20:4n-6) in FFA, TAG, and PC (P0.05 for all) in NASH. Eicosapentanoic acid (20:5n-3) and docosahexanoic acid (22:6n-3) were decreased in TAG in NASH. The n-6:n-3 FFA ratio increased in NASH (P0.05).NAFLD is associated with numerous changes in the lipid composition of the liver. The potential implications are discussed.

The patterns of fat distribution and their relationship to severity of nonalcoholic fatty liver disease (NAFLD) are unknown. The objectives of this study were to define the fat distribution patterns and their relationship to histological severity and metabolic parameters in subjects with NAFLD. Anthropometric indices and total body fat were measured in 123 subjects. Fat distribution patterns were defined as: general, abdominal, limb, truncal, and dorsocervical lipohypertrophy (DCL) a novel finding in NAFLD. Eighty-one (66%) of the subjects were obese, and 94 (76%) had abdominal obesity. Thirty-five (28.5%) had DCL. Whereas body mass index (BMI) correlated best with the presence of diabetes (r 0.22, P < 0.05), waist circumference (WC) correlated best with hypertension (r 0.2, P < 0.05), hypertriglyceridemia (r 0.37, P < 0.001), and insulin resistance (homeostasis model of assessment for insulin resistance [r 0.68, P < 0.0001]). None of the patterns of fat distribution were significantly associated with severity of hepatic steatosis. Abdominal obesity (WC) correlated with inflammation (r 0.2, P < 0.05) only. DCL correlated significantly with the severity of all histological parameters except steatosis. Whereas DCL was the single greatest contributor to the variability in severity of histological parameters, a model combining BMI, WC, and DCL showed the greatest contribution to the variability in severity of individual histological parameters. The addition of steatosis grade to the model significantly increased its contribution to the range of lobular inflammation. Conclusion: WC predicts metabolic risk profile with the most significance. However, DCL is most strongly associated with severity of steatohepatitis. WC and BMI added modestly to the contribution of DCL to severity of nonalcoholic steatohepatitis. (HEPATOLOGY 2007;46:1091-1100.)

Background: Interatrial block (IAB; P wave ≥110 ms) is highly prevalent and is strongly associated with atrial tachyarrhythmias and left atrial dysfunction, making it a potential embolic risk. Methods and Results: Among 293 neurological admissions over 2 years, 85 patients were diagnosed with embolic strokes and 208 with nonembolic strokes. Patients were then matched for stroke risk factors and evaluated for IAB. Eighty-eight percent of probable embolic stroke patients showed sinus rhythm, demonstrating a 61% IAB prevalence. Only hypertension (P < 0.001; r = 0.3) and IAB (P < 0.006; r = 0.2) were significant and directly correlated. Conclusion: IAB could indeed be a novel risk for embolic strokes and further investigation is warranted.

Zinc deficiency has been observed in cirrhosis, but management guidelines do not address screening for zinc deficiency. We aim to determine the prevalence of zinc deficiency in different stages of cirrhosis and to correlate zinc levels with complications of cirrhosis and clinical outcomes. Patients who had a diagnosis of cirrhosis and had serum zinc levels drawn from 2007 to 2011 were identified. Demographics, laboratory data, presence of ascites, encephalopathy, and infection were obtained; Child-Pugh and MELD scores were calculated. Stata software was used for data analysis. A total of 163 patients were included in the study.The median serum zinc level was 0.47 mcg/ml (IQR 0.37-0.63); 83 % of patients were zinc deficient. Zinc deficiency was more prevalent in patients with Child-Pugh score B or C, and with MELD scores ≥15. Zinc levels were lower in alcoholic, hepatitis C, and cholestatic diseases than in other etiologies of liver disease. Zinc levels correlated with INR (r = -0.56, p0.001), bilirubin (r = -0.51, p0.001), and albumin (r = 0.68, p0.001), and were lower in patients with ascites (0.40 vs. 0.57 mcg/ml, p0.001), encephalopathy (0.40 vs. 0.53 mcg/ml, p0.001), diuretic use (0.45 vs. 0.535 mcg/ml, p = 0.005), and infection (0.32 vs. 0.51 mcg/ml, p0.001). Ascites (p = 0.044) and infection (p = 0.009) were independently associated with zinc levels. Zinc-deficient patients had lower transplant-free survival rates than non-deficient patients.Zinc deficiency is highly prevalent in cirrhotic patients with Child-Pugh score B or C, and with MELD score ≥15. Zinc deficiency also correlates with disease severity, infection, and a worse transplant-free survival. Screening for zinc deficiency should be considered in this subset of patients.

Poor brain reserve in alcoholic cirrhosis could worsen insight regarding disease severity and increase the patients' vulnerability toward further deterioration. The aim of this study was to analyze brain reserve in abstinent alcoholic cirrhotic (Alc) patients compared to nonalcoholic cirrhotic (Nalc) patients in the context of hepatic encephalopathy (HE) and to evaluate relative change in brain reserve between groups over time and before and after elective transjugular intrahepatic portosystemic shunt (TIPS) placement. The cross-sectional study included 46 Alc and 102 Nalc outpatients with or without HE. Cognitive tests were followed by magnetic resonance imaging (MRI), including proton magnetic resonance spectroscopy (1 H-MRS), diffusion tensor imaging, and T1-weighted imaging. The prospective study included 1H-MRS on a subset of 10 patients before and after TIPS placement. Another subset of 26 patients underwent (1) H-MRS at least 1 year apart. For the cross-sectional study, Alc patients were worse on cognitive tests than Nalc patients. MRI results suggest a greater effect of hyperammonemia, brain edema, and significantly higher cortical damage in Alc as compared to Nalc patients. The effect of HE status on cognitive tests and brain reserve was more marked in the Nalc than in the Alc group. For the TIPS study, Nalc patients showed a greater adverse relative change after TIPS compared to the Alc group. At 1-year follow-up, both groups remained stable between the 2 visits. However, Alc patients continued to show poor brain reserve compared to Nalc patients over time. In conclusion, Alc patients, despite abstinence, have a poor brain reserve, whereas Nalc patients have a greater potential for brain reserve deterioration after HE and TIPS. Information regarding the brain reserve in cirrhosis could assist medical teams to refine their communication and monitoring strategies for different etiologies.

Background Interatrial block (IAB; P waves ≥ 110 milliseconds), the conduction delay between the right (RA) and left atrium (LA), is depicted on the electrocardiogram (ECG) as prolonged, often bifid (“notched”), P waves with distinguishable RA and LA components. Although electrophysiologic (EP) studies give some insight on how RA and LA components are depicted on the surface ECG in normal conduction, few if at all any, have conclusively demonstrated this correlation with IAB. Using existing EP knowledge, we investigated if such P-wave markers on bedside ECGs exist in IAB and appraised their utility in IAB recognition. Methods We reviewed the medical records of patients admitted to a general hospital from December 1, 2004, to December 15, 2004. Of those, 151 patients had been admitted for nonacute presentations and were screened with 12-lead ECGs. Thirty-eight ECGs were excluded for nonsinus and paced rhythms, severe motion artifact, errors in lead placement, absence of adequate patient identification, and duplicate patient admissions after discharge. The remaining 113 ECGs were then evaluated for IAB. Sixty-three patients who did not have IAB formed the control (group A), whereas of the remaining 50 patients with IAB, 24 who had past ECGs for comparison formed group B1 and 26 without past ECGs formed group B2. Groups were compared for common clinical comorbidities, whereas sensitivity and specificity were calculated for significant P-wave markers. P values were also calculated, with a value of

Interatrial block (IAB) (P wave > or =110 milliseconds) is a potent correlate of atrial tachyarrhythmias, left atrial electromechanical dysfunction, and embolism. IAB has been demonstrated to be highly prevalent in the general hospital population, but no investigation has addressed this in the elderly community outside the hospital. We appraised the prevalence of IAB in a service of the Program of All-Inclusive Care for the Elderly (PACE), the Elder Service Plan (ESP). Of the 202 ESP members in Worcester, MA, 167 (ages 61-103 years; female 81.4%) who had current 12-lead electrocardiograms were evaluated for IAB, and an age-based comparison was made between those with and without IAB. Of those patients with current electrocardiograms, 148 (88.6%) showed sinus rhythm and 72 (48.6%) depicted IAB: 20% in patients aged 60-69 years, 39.5% aged 70-79 years, 56.8% aged 80-89 years, and 50% in those 90 years and older. Given its sequelae of anatomic and pathophysiologic consequences, prompt recognition of IAB in a high-risk group such as that in the PACE community (48.6% prevalence) is important, especially for anticipation of atrial fibrillation and possible embolism.

Up to 30% chronic heavy drinkers develop a spectrum of severe alcoholic liver diseases, including alcoholic hepatitis (AH). Alcohol-induced impairment of intestinal integrity and microbial translocation into the portal vein lead to immune activation and play a major role in the pathogenesis of AH. To better understand why AH develops only in some heavy drinkers and the effect of alcohol abstinence on immunity, we conducted a prospective study to compare plasma LPS levels and peripheral blood immunoprofiles between 68 AH patients and 65 heavy drinkers without liver disease (HDC) who were followed up to 12 months. Plasma samples were also obtained from 31 health donors (HD). Plasma LPS was detected in a higher portion of AH patients than HDC (80% vs 49%) at baseline, and in only 8% HD. However, LPS levels were not different between AH an HDC subjects with detectable LPS. Compared with HDC, AH patients had higher baseline plasma levels of sCD14, sCD163, sICAM-1, sVCAM-1, IL-22, TNF-α, IL-8, IP10, IL-4, IL-6, IL-9, IL-10, FGF2, IL-7, IL-15, and TGF-α, but lower levels of the anti-inflammatory chemokine MDC. AH patients also had more activated, yet dysfunctional monocytes, T cells, and B cells as they expressed higher levels of CD38 and CD69, but lower levels of HLA-DR, CD80, and CD86. In spite of having significant bacterial translocation, HDC showed little evidence of immune activation. With alcohol abstinence, levels of many dysregulated immune markers normalized in AH patients. However, TNF-α, IL-8, IL-10, sCD163, and sVCAM-1 levels remained higher. Conclusion AH patients were more susceptible to alcohol-induced bacterial translocation and immune activation. Alcohol abstinence reduced but did not fully reverse immunological abnormalities.

Despite the high prevalence of covert hepatic encephalopathy (CHE) in cirrhotics without previous overt HE (OHE), its independent impact on predicting clinically relevant outcomes is unclear. The aim of this study was to define the impact of CHE on time to OHE, hospitalization, and death/transplant in prospectively followed up patients without previous OHE.Outpatient cirrhotics without OHE were enrolled and were administered a standard paper-pencil cognitive battery for CHE diagnosis. They were systematically followed up and time to first OHE development, hospitalization (liver-related/unrelated), and transplant/death were compared between CHE and no-CHE patients at baseline using Cox regression.A total of 170 cirrhotic patients (55 years, 58% men, 14 years of education, Model for End-Stage Liver Disease (MELD 9), 53% hepatitis C virus (HCV), 20% nonalcoholic etiology) were included, of whom 56% had CHE. The entire population was followed up for 13.0 ± 14.6 months, during which time 30% developed their first OHE episode, 42% were hospitalized, and 19% had a composite death/transplant outcome. Age, gender, etiology, the MELD score, and CHE status were included in Cox regression models for time to first OHE episode, hospitalization, death, and composite death/transplant outcomes. On Cox regression, despite controlling for MELD, those with CHE had a higher risk of developing OHE (hazard ratio: 2.1, 95% confidence interval 1.01-4.5), hospitalization (hazard ratio: 2.5, 95% confidence interval 1.4-4.5), and death/transplant (hazard ratio: 3.4, 95% confidence interval 1.2-9.7) in the follow-up period.Covert HE is associated with worsened survival and increased risk of hospitalization and OHE development, despite controlling for the MELD score. Strategies to detect and treat CHE may improve these risks.

Background & Aims In patients with cirrhosis, sleep disturbances are assumed to result from hepatic encephalopathy (HE). The effects of obstructive sleep apnea (OSA) on cognition, sleep parameters, or driving in patients with cirrhosis are unclear. Methods We performed a cross-sectional and prospective study of 118 subjects. Subjects were assigned to 1 of 4 groups: those with OSA and cirrhosis (without hepatic encephalopathy or ascites, n = 34), those with cirrhosis only (n = 30), those with OSA only (n = 29), and those without OSA or cirrhosis (controls, n = 25). None of the OSA patients were receiving continuous positive airway pressure (CPAP) therapy. Subjects underwent cognitive testing (paper–pencil tests for psychomotor speed and attention, as well as executive function tests), sleep assessment (daytime sleepiness and night-time sleep quality), and a monotonous driving simulation (worsening lane deviations over time indicated poor performance). We also tested patients with OSA, with cirrhosis (n = 10) and without cirrhosis (n = 7), before and after CPAP therapy. Results Daytime sleepiness and sleep quality were worse in subjects in the OSA groups (with or without cirrhosis) than subjects with cirrhosis alone or controls. Of subjects with only OSA, 36% had impaired psychomotor speed and attention, compared with more than 60% of subjects in both cirrhosis groups. In contrast, executive function was uniformly worse in subjects with OSA, with or without cirrhosis, than groups without OSA. Simulator performance (lane deviations) worsened over time in both OSA groups. CPAP therapy significantly increased executive function and sleep quality, and reduced simulator lane deviations and sleepiness, in OSA subjects with and without cirrhosis. After CPAP therapy, performance on the paper–pencil test improved significantly only in subjects with OSA without cirrhosis. Conclusions OSA should be considered in evaluating sleep impairment in patients with cirrhosis. In patients with cirrhosis and OSA, psychomotor speed and attention issues likely are related to cirrhosis, whereas executive function and simulator performance are affected by OSA. CPAP therapy improves executive function and simulator performance in patients with OSA, regardless of cirrhosis.

SummaryBackground Safety of individual probiotic strains approved under Investigational New Drug (IND) policies in cirrhosis with minimal hepatic encephalopathy (MHE) is not clear. Aim The primary aim of this phase I study was to evaluate the safety, tolerability of probiotic Lactobacillus GG (LGG) compared to placebo, while secondary ones were to explore its mechanism of action using cognitive, microbiome, metabolome and endotoxin analysis in MHE patients. Methods Cirrhotic patients with MHE patients were randomised 1:1 into LGG or placebo BID after being prescribed a standard diet and multi-vitamin regimen and were followed up for 8 weeks. Serum, urine and stool samples were collected at baseline and study end. Safety was assessed at Weeks 4 and 8. Endotoxin and systemic inflammation, microbiome using multi-tagged pyrosequencing, serum/urine metabolome were analysed between groups using correlation networks. Results Thirty MHE patients (14 LGG and 16 placebo) completed the study without any differences in serious adverse events. However, self-limited diarrhoea was more frequent in LGG patients. A standard diet was maintained and LGG batches were comparable throughout. Only in the LGG-randomised group, endotoxemia and TNF-α decreased, microbiome changed (reduced Enterobacteriaceae and increased Clostridiales Incertae Sedis XIV and Lachnospiraceae relative abundance) with changes in metabolite/microbiome correlations pertaining to amino acid, vitamin and secondary BA metabolism. No change in cognition was found. Conclusions In this phase I study, Lactobacillus GG is safe and well-tolerated in cirrhosis and is associated with a reduction in endotoxemia and dysbiosis.

The fasting-activated longevity protein sirtuin 1 (SirT1, ref. 1) promotes gluconeogenesis in part, by increasing transcription of the key gluconeogenic genes pepck1 and g6pase2,3, through deacetylating PGC-1α and FOXO1 (ref. 4). In contrast, signal transducer and activator of transcription 3 (STAT3) inhibits glucose production by suppressing expression of these genes5,6. It is not known whether the inhibition of gluconeogenesis by STAT3 is controlled by metabolic regulation. Here we show that STAT3 phosphorylation and function in the liver were tightly regulated by the nutritional status of an animal, through SirT1-mediated deacetylation of key STAT3 lysine sites. The importance of the SirT1-STAT3 pathway in the regulation of gluconeogenesis was verified in STAT3-deficient mice in which the dynamic regulation of gluconeogenic genes by nutritional status was disrupted. Our results reveal a new nutrient sensing pathway through which SirT1 suppresses the inhibitory effect of STAT3, while activating the stimulatory effect of PGC-1α and FOXO1 on gluconeogenesis, thus ensuring maximal activation of gluconeogenic gene transcription. The connection between acetylation and phosphorylation of STAT3 implies that STAT3 may have an important role in other cellular processes that involve SirT1.

Sex and sex hormones can affect responses of patients with nonalcoholic fatty liver disease (NAFLD) to metabolic stress and development of hepatocyte injury and inflammation. We collected data from 3 large US studies of patients with NAFLD (between October 2004 and June 2013) to assess the association between histologic severity and sex, menopause status, synthetic hormone use, and menstrual abnormalities in 1112 patients with a histologic diagnosis of NAFLD. We performed logistic or ordinal logistic regression models, adjusting for covariates relevant to an increase of hepatic metabolic stress. We found that pre-menopausal women were at an increased risk of lobular inflammation, hepatocyte ballooning, and Mallory-Denk bodies than men and also at an increased risk of lobular inflammation and Mallory-Denk bodies than post-menopausal women (P

Minimal hepatic encephalopathy (MHE) detection is difficult because of the unavailability of short screening tools. Therefore, MHE patients can remain undiagnosed and untreated. The aim of this study was to use a Stroop smartphone application (app) (EncephalApp_Stroop) to screen for MHE. The app and standard psychometric tests (SPTs; 2 of 4 abnormal is MHE, gold standard), psychometric hepatic encephalopathy score (PHES), and inhibitory control tests (ICTs) were administered to patients with cirrhosis (with or without previous overt hepatic encephalopathy; OHE) and age-matched controls from two centers; a subset underwent retesting. A separate validation cohort was also recruited. Stroop has an "off" state with neutral stimuli and an "on" state with incongruent stimuli. Outcomes included time to complete five correct runs as well as number of trials needed in on (Ontime) and off (Offtime) states. Stroop results were compared between controls and patients with cirrhosis with or without OHE and those with or without MHE (using SPTs, ICTs, and PHES). Receiver operating characteristic analysis was performed to diagnose MHE in patients with cirrhosis with or without previous OHE. One hundred and twenty-five patients with cirrhosis (43 previous OHE) and 134 controls were included in the original cohort. App times were correlated with Model for End-Stage Liver Disease (Offtime: r = 0.57; Ontime: r = 0.61; P0.0001) and were worst in previous OHE patients, compared to the rest and controls. Stroop performance was also significantly impaired in those with MHE, compared to those without MHE, according to SPTs, ICTs, and PHES (all P0.0001). A cutoff of274.9 seconds (Ontime plus Offtime) had an area under the curve of 0.89 in all patients and 0.84 in patients without previous OHE for MHE diagnosis using SPT as the gold standard. The validation cohort showed 78% sensitivity and 90% specificity with the274.9-seconds Ontime plus Offtime cutoff. App result patterns were similar between the centers. Test-retest reliability in controls and those without previous OHE was good; a learning effect on Ontime in patients with cirrhosis without previous OHE was noted.The Stroop smartphone app is a short, valid, and reliable tool for screening of MHE.

The aim of this study was to compare conventional miniplate (Champy's) and 3-dimensional miniplate fixation in the management of mandibular fracture.Prospective study.The study was carried out in the Department of Oral and Maxillofacial Surgery, Govt. Dental College, Pt. B.D. Sharma University of Health Sciences, Rohtak, India.A prospective randomized clinical trial was carried out in 50 patients. Patients were randomly assigned to receive a 2.0-mm 3-dimensional miniplate (group A) or a 2.0-mm conventional miniplate (group B). All patients were followed up for 12 weeks postoperatively. Complications were analyzed according to the type of plate used and the site of fracture.Twenty-eight fracture sites were treated with the 3-dimensional miniplate and 28 with the conventional miniplate. Five complications occurred, representing 8.9% of the total. Two complications occurred in group A and 3 in group B, with complication rates equaling 7.14% and 10.71%, respectively. When comparing the overall complication rates according to plates used, the χ(2) test showed no statistically significant difference between the 2 groups (P.05).No major difference in terms of treatment outcome is observed in both systems, and both are equally effective in managing mandibular fracture.

Summary Background The subjectivity of the West-Haven criteria (WHC) hinders hepatic encephalopathy (HE) evaluation. The new HE classification has emphasised assessment of orientation. The modified-orientation log (MO-log, eight questions, scores 0–24; 24 normal) is adapted from a validated brain injury measure. Aim To validate MO-log for HE assessment in cirrhosis. Methods Cirrhotics admitted with/without HE were administered MO-log. We collected cirrhosis/HE details, admission/daily MO-logs and WHC (performed by different examiners), time to reach normal mentation (MO-log ≥23) and MO-log/WHC change (Δ) over day 1. Outcomes were in-hospital mortality, duration to normal mentation and length-of-stay (LOS). Regressions were performed for each outcome. MO-log inter-rater reliability was measured. Results Ninety-six HE (55 ± 8 years, MELD 21) and 20 non-HE (54 ± 5 years, MELD 19) in-patients were included. In HE patients, median admission WHC was 3 (range 1–4). Mean MO-log was 12 ± 8 (range 0–22). Their LOS was 6 ± 5 days and 13% died. Time to reach normal mentation was 2.4 ± 1.7 days. Concurrent validity: there was a significant negative correlation between admission MO-log and WHC (r = −0.79, P